What is the mechanism of action, peak plasma concentration, and duration of action of Concerta (methylphenidate) for Attention Deficit Hyperactivity Disorder (ADHD)?

Concerta (Methylphenidate) for ADHD: Mechanism, Pharmacokinetics, and Duration

Mechanism of Action

Concerta (methylphenidate) blocks the reuptake of norepinephrine and dopamine into the presynaptic neuron and increases the release of these monoamines into the extraneuronal space. 1

• Methylphenidate is a central nervous system (CNS) stimulant that functions primarily as a dopamine and norepinephrine transporter inhibitor 1
• The d-threo enantiomer is more pharmacologically active than the l-threo enantiomer 1
• Additional mechanisms include agonist activity at the serotonin type 1A receptor and redistribution of the vesicular monoamine transporter 2 2
• By enhancing dopamine and norepinephrine signaling, methylphenidate increases the efficiency of prefrontal cortex activity and optimizes executive and attentional function 2

Peak Plasma Concentration

Concerta reaches peak plasma concentrations 7 to 9 hours after administration, with effects beginning within 1 to 2 hours. 3, 4

• The OROS (osmotic pump) delivery system produces a rapid initial rise followed by gradually increasing plasma concentrations that peak at 7-9 hours post-dose 4
• This ascending plasma profile differs markedly from immediate-release methylphenidate, which peaks at 1-2 hours 1, 5
• The delayed peak was specifically designed to overcome acute tolerance (tachyphylaxis) that occurs with standard formulations 4
• For comparison, immediate-release methylphenidate oral solution reaches Cmax of approximately 9.1 ng/mL at 1-2 hours 1

Duration of Action

Concerta provides 10 to 12 hours of continuous symptom control after a single morning dose. 3, 4, 6

• The osmotic pump system delivers methylphenidate in an ascending pattern throughout the day, maintaining therapeutic effects for a full 12-hour period 3, 4
• Clinical studies demonstrate that Concerta is equivalent to immediate-release methylphenidate given three times daily in both laboratory and natural school settings 6
• The 18 mg dose of Concerta is approximately equivalent to methylphenidate 5 mg three times daily 3
• Effects persist into the evening hours, with parent ratings showing continued behavioral improvement 6

Clinical Pharmacokinetic Profile

The unique ascending delivery pattern of Concerta prevents the symptom deterioration that typically occurs across the day with shorter-acting formulations. 4, 6

• Concerta utilizes OROS technology with an overcoat providing immediate release of 22% of the dose, followed by controlled release of the remaining 78% 4
• The mean terminal half-life of methylphenidate is approximately 2.7 hours, but the delivery system extends clinical effects well beyond this 1
• Plasma protein binding is 10% to 33%, with a volume of distribution of 2.65 ± 1.11 L/kg for d-methylphenidate 1
• Methylphenidate is metabolized primarily by deesterification to ritalinic acid, which has minimal pharmacologic activity, with about 90% of radioactivity recovered in urine 1

Important Clinical Considerations

Food delays absorption but does not significantly reduce bioavailability—Concerta can be taken with or without food. 1

• High-fat meals increase Cmax and AUC by approximately 13% and 25% respectively, and delay Tmax by about 1 hour 1
• The gradual onset (1-2 hours) means Concerta should not be expected to provide immediate symptom control like immediate-release formulations 3, 4
• For patients requiring coverage beyond 12 hours, short-acting stimulant boosters can be added in late afternoon, though timing is critical to avoid insomnia 3
• Individual response to methylphenidate formulations is idiosyncratic, with approximately 40% of patients responding to both methylphenidate and amphetamine, and 40% responding to only one 3